Trends in urine biomarker discovery for urothelial bladder cancer: DNA, RNA, or protein?

Urothelial bladder cancer is a complex disease displaying a landscape of heterogenous molecular subtypes, mutation profiles and clinical presentations. Diagnosis and surveillance rely on flexible cystoscopy which has high accuracy, albeit accompanied by a high-cost burden for healthcare providers and discomfort for patients. Advances in "omic" technologies and computational biology have provided insights into the molecular pathogenesis of bladder cancer and provided powerful tools to identify markers for disease detection, risk stratification, and predicting responses to therapy. To date, numerous attempts have been made to discover and validate diagnostic biomarkers that could be deployed as an adjunct to the cystoscopic diagnosis and long-term surveillance of bladder cancer. We report a comprehensive literature analysis using PubMed to assess the changing trends in investigating DNA, RNA, or proteins as diagnostic urinary biomarkers over a period of 5 decades: 1970-2020. A gradual shift has been observed in research away from protein biomarkers to nucleic acids including different classes of RNA, and DNA methylation and mutation markers. Until 2000, publications involving protein biomarker discovery constituted 87% of the total number of research articles with DNA comprising 6% and RNA 7%. Since 2000 the proportion of protein biomarker articles has fallen to 40%, and DNA and RNA studies increased to 32% and 28%, respectively. Clearly research focus, perhaps driven by technological innovation, has shifted from proteins to nucleic acids. We optimistically hypothesise that, following thorough validation, a clinically useful detection test for bladder cancer based on a panel of DNA or RNA markers could become reality within 5-10 years.